We propose a series of interrelated studies of the pharmacokinetics, pharmacodynamics of furosemide. These studies should further our insight into the pathophysiology of renal salt handling in various disease states, increase our understanding of the pharmacology of furosemide, and provide more rational guidelines for the use of furosemide in a variety of settings. The determinants of the relationship of the dose of furosemide to its effect are poorly defined. By studying the relationship in normal subjects of natriuresis and diuresis to the concentration of furosemide in different biologic fluids (saliva, serum, urine), we hope to define a clear relationship between dose, concentration of the drug in a body compartment, and drug effect. Because furosemide has an intraluminal site of action, we predict urine concentrations or amounts of furosemide will correlate with effect. After defining these relationships in normals, we propose a logical extension to similar studies in different disease states and therapeutic settings. By studying patients with various degrees of uremia and subjects receiving other agents which affect delivery of furosemide to its active site (probenecid, indomethacin), we can assess the role of modulators of the amount of furosemide reaching its site of action and diuretic effect. By studying patients with disease states associated with changes in delivery of sodium to the loop of Henle and with hemodynamic changes (congestive heart failure and renal transplant recipients), we hope to access determinants of furosemide's effects other than and in addition to changes in delivery of the diuretic to its site of action. By comparing the effect of probenecid to that of indomethacin on the diuretic effects of furosemide, we hope to more clearly differentiate the importance of pharmacokinetic interactions with these drugs from affects on possible mediators of the diuretic effects of furosemide (prostaglandins). With these studies we should be able to more clearly define the relationship between the dose of furosemide and its effect in a variety of disease states. By so doing we should gain insight into the pathophysiology of these diseases and derive therapeutic guidelines for the use of furosemide in a variety of settings.